Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
  • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
  • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
  • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
  • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
  • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
  • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines

Definitions

• the present invention relates to piperazine compounds of the general formula I defined below and to their use as herbicides. Moreover, the invention relates to compositions for crop protection and to a method for controlling unwanted vegetation.
• the thaxtomins A and B (King R. R. et al., J. Agric. Food Chem. (1992) 40, 834-837), which are produced by the plant pathogen S. scabies, are natural products having a central piperazine-2,5-dione ring which carries a 4-nitroindol-3-ylmethyl radical in the 3-position and an optionally OH-substituted benzyl radical in the 2-position. Because of their plant-damaging activity, this class of compounds was also examined for a possible use as herbicides (King R. R. et al., J. Agric. Food Chem. (2001) 49, 2298-2301).
• EP-A 181152 and EP-A 243122 describe structurally similar piperazine compounds and their use as antagonists of the platelet activating factor.
• WO 99/48889, WO 01/53290 and WO 2005/011699 describe 2,5-diketopiperazine compounds having in one of the 3- and 6-positions a 4-imidazolyl radical which is attached via a methylene or methyne group and in the other 3- or 6-position a benzyl or benzylidene radical. These compounds have antitumor activity.
• R is H or methyl
• the present invention also provides the use of piperazine compounds of the general formula I or the agriculturally useful salts of piperazine compounds of the formula I as herbicides, i.e. for controlling harmful plants.
• the present invention also provides compositions comprising at least one piperazine compound of the formula I or an agriculturally useful salt of I and auxiliaries customary for formulating crop protection agents.
• the present invention furthermore provides a method for controlling unwanted vegetation where a herbicidally effective amount of at least one piperazine compound of the formula I or an agriculturally useful salt of I is allowed to act on plants, their seeds and/or their habitat.
• the invention relates to processes and intermediates for preparing compounds of the formula I.
• the compounds of the formula I may have the cis or the trans configuration.
• the invention provides both the pure cis isomers and trans isomers and their mixtures.
• the compounds of the formula I have a center of chirality each. Accordingly, the compound I exists in the form of four different configurational isomers (S,S)-I, (R,R)-I, (R,S)-I and (S,R)-I where in each case two of these configurational isomers are like image and mirror image to one another, as shown in the figure below.
• the compound I may be present in the form of the pure enantiomers, and also as enantiomer mixtures, for example as a mixture of (S,S)-I with (R,R)-I or as a mixture of (R,S)-I with (S,R)-I, or as diastereomer mixtures, for example as a mixture of all four diastereomers.
• the invention provides both the pure enantiomers or diastereomers and their mixtures.
• the compounds of the formula I may also be present in the form of their agriculturally useful salts, the nature of the salt generally being immaterial. Suitable salts are, in general, the salts of those cations or the acid addition salts of those acids whose cations and anions, respectively, which have no adverse effect on the herbicidal action of the compounds I.
• Suitable cations are in particular ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium and magnesium, and of the transition metals, preferably manganese, copper, zinc and iron, and also ammonium, where, if desired, one to four hydrogen atoms may be replaced by C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, phenyl or benzyl, preferably ammonium, dimethylammonium, diisopropylammonium, tetramethylammonium, tetrabutylammonium, 2-(2-hydroxyeth-1-oxy)eth-1-yl-ammonium, di(2-hydroxyeth-1-yl)ammonium, trimethylbenzyl
• Anions of useful acid addition salts are primarily chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C 1 -C 4 -alkanoic acids, preferably formate, acetate, propionate and butyrate.
• organic moieties mentioned for the substituents of the compounds according to the invention are collective terms for individual enumerations of the specific group members.
• halogenated substituents preferably carry one to five identical or different halogen atoms, in particular fluorine atoms or chlorine atoms.
• halogen denotes in each case fluorine, chlorine, bromine or iodine.
• alkyl and also the alkyl moieties for example, in alkoxy, alkylamino, dialkylamino, N-alkylsulfonylamino, alkylaminosulfonylamino, dialkylaminosulfonylamino, N-(alkenyl)-N-(alkyl)-amino, N-(alkynyl)-N-(alkyl)-amino, N-(alkoxy)-N-(alkyl)-amino: saturated straight-chain or branched hydrocarbon radicals having one or more carbon atoms, for example 1 to 2, 1 to 4 or 1 to 6 carbon atoms, for example C 1 -C 6 -alkyl, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-
• alkyl denotes small alkyl groups such as C 1 -C 4 -alkyl. In another embodiment according to the invention, alkyl denotes relatively large alkyl groups such as C 5 -C 6 -alkyl.
• Haloalkyl an alkyl radical as mentioned above whose hydrogen atoms are partially or fully substituted by halogen atoms such as fluorine, chlorine, bromine and/or iodine, for example chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoroprop
• Cycloalkyl and also the cycloalkyl moieties for example, in cycloalkoxy or cycloalkylcarbonyl: monocyclic saturated hydrocarbon groups having three or more carbon atoms, for example 3 to 6 carbon ring members, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Alkenyl and also alkenyl moieties for example in alkenylamino, alkenyloxy, N-(alkenyl)-N-(alkyl)-amino, N-(alkenyl)-N-(alkoxy)-amino: monounsaturated straight-chain or branched hydrocarbon radicals having two or more carbon atoms, for example 2 to 4, 2 to 6, or 3 to 6 carbon atoms, and a double bond in any position, for example C 2 -C 6 -alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-
• Cycloalkenyl monocyclic, monounsaturated hydrocarbon groups having from 5 to 6, preferably 5 to 6, carbon ring members, such as cyclopenten-1-yl, cyclopenten-3-yl, cyclohexen-1-yl, cyclohexen-3-yl, cyclohexen-4-yl.
• Alkynyl and also alkynyl moieties for example in alkynyloxy, alkynylamino, N-(alkynyl)-N-(alkyl)-amino or N-(alkynyl)-N-(alkoxy)-amino: straight-chain or branched hydrocarbon groups having two or more carbon atoms, for example 2 to 4, 2 to 6, or 3 to 6 carbon atoms, and a triple bond in any position, for example C 2 -C 6 -alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl
• Alkoxy alkyl, as defined above, which is attached via an oxygen atom: for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy or 1-ethyl-2-methylpropoxy.
• Aryl monocyclic or polycyclic aromatic hydrocarbon radicals having 6 to 14 carbon atoms, such as phenyl, naphthyl, anthracenyl or phenanthrenyl, preferably phenyl or naphthyl.
• a 5- or 6-membered heterocyclic radical a heterocyclic radical which has 5 or 6 ring atoms, 1, 2, 3 or 4 ring atoms being heteroatoms selected from the group consisting of O, S and N, where the heterocyclic radical is saturated, partially unsaturated or aromatic.
• heterocyclic radicals are:
• heterocycles mentioned above may be substituted in the manner stated.
• Sulfur atoms in the heterocycles mentioned above may be oxidized to S ⁇ O or S( ⁇ O) 2 .
• variables of the compounds of the formula I have the meanings below, these meanings—both on their own and in combination with one another—being particular embodiments of the compounds of the formula I:
• R 1 is in particular cyano, nitro or a 5- or 6-membered heteroaromatic radical as defined above which preferably has either 1, 2, 3 or 4 nitrogen atoms or 1 oxygen or 1 sulfur atom and, if appropriate, 1 or 2 nitrogen atoms as ring members and which is unsubstituted or may have 1 or 2 substituents selected from R 1a .
• R 1 is cyano or nitro.
• R 1 is a 5- or 6-membered heteroaromatic radical as defined above which preferably has either 1, 2, 3 or 4 nitrogen atoms or 1 oxygen or 1 sulfur atom and, if appropriate, 1 or 2 nitrogen atoms as ring members and which is unsubstituted or may have 1 or 2 substituents selected from R 1a .
• heteroaromatic radicals are pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-2
• the radical R 2 is preferably hydrogen, fluorine, chlorine, C 1 -C 2 -alkyl, C 1 -C 2 -fluoroalkyl, ethenyl, C 1 -C 2 -alkoxy or C 1 -C 2 -fluoroalkoxy, in particular fluorine, chlorine, methyl, ethyl, methoxy, ethenyl or trifluoromethoxy.
• R 2 is especially preferred hydrogen, fluorine or chlorine.
• R 2 is halogen, in particular chlorine or fluorine, which is located in the ortho-position to the point of attachment of the phenyl ring.
• R 3 is halogen
• R 3 is hydrogen.
• R 4 is preferably methyl.
• R 5 is preferably hydrogen, methyl or ethyl, especially methyl.
• R 5 is a group C( ⁇ O)R 51 in which R 51 has one of the meanings given above and is in particular hydrogen, C 1 -C 4 -alkyl, especially methyl or ethyl, or C 1 -C 4 -haloalkyl, especially C 1 -C 2 -fluoroalkyl, such as trifluoromethyl.
• R 6 is preferably C 1 -C 3 -alkyl, or C 1 -C 2 -fluoroalkyl, in particular methyl, ethyl, n-propyl, or trifluoromethyl, and especially methyl or ethyl.
• radicals R 7 and R 8 are hydrogen.
• R 9 is a radical different from hydrogen
• R 9 is hydrogen.
• R 10 is preferably hydrogen.
• R 11 is preferably hydrogen.
• R 12 is preferably hydrogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 have one of the meanings given above, in particular the meanings given as being preferred.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 independently of one another, but preferably in combination, have in particular the meanings below:
• the compounds of the formula I have a center of chirality each at the carbon atoms of the 3- and the 6-position of the piperazine ring. Preference is given to those compounds of the formula I in which the benzylic groups at the 3- and the 6-position have a cis configuration with respect to the piperazine ring, i.e. to the S,S enantiomer (S,S)-I and the R,R enantiomer (R,R)-I, and also their mixtures.
• a particularly preferred embodiment of the invention relates to the S,S enantiomer of the formula (S,S)-I, and also to enantiomer mixtures and diastereomer mixtures of I in which the S,S enantiomer is the main component and is present in an amount of preferably at least 70%, in particular at least 80% and especially at least 90% of the compound I.
• Another embodiment which is likewise preferred relates to a racemic mixture of the S,S enantiomer (S,S)-I with the R,R enantiomer (R,R)-I.
• Another embodiment of the invention relates to the R,R enantiomer of the formula (R,R)-I, and also to enantiomer mixtures and diastereomer mixtures of I in which the R,R enantiomer is the main component and is present in an amount of preferably at least 70%, in particular at least 80% and especially at least 90% of the compound I.
• Another embodiment of the invention relates to the agriculturally suitable salts of the enantiomers (R,R)-I and to enantiomer mixtures and diastereomer mixtures of the salts in which the R,R enantiomer is the main component and is present in an amount of preferably at least 70%, in particular at least 80% and especially at least 90% of the compound I.
• Another embodiment which is likewise preferred relates to a racemic mixture of the S,S enantiomer (S,S)-Ia with the R,R enantiomer (R,R)-Ia.
• Another embodiment of the invention relates to the pure enantiomers of the formula (R,R)-Ia indicated below in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 9 have one of the meanings given above, in particular one of the meanings given as being preferred or as being particularly preferred, and also to enantiomer mixtures and diastereomer mixtures of Ia in which the R,R enantiomer is the main component and is present in an amount of preferably at least 70%, in particular at least 80% and especially at least 90% of the compound Ia.
• Another embodiment of the invention relates to the agriculturally suitable salts of the enantiomers (R,R)-Ia and to enantiomer mixtures and diastereomer mixtures of the salts in which the salt of the S,S enantiomer is the main component and is present in an amount of preferably at least 70%, in particular at least 80% and especially at least 90% of the salt of Ia.
• process A which comprises the following steps:
• step ii) or iiia) can be carried out analogously to standard processes of alkylation, for example according to the methods described by I. O. Donkor et al., Bioorg. Med. Chem. Lett. 11 (19) (2001), 2647-2649, B. B. Snider et al., Tetrahedron 57 (16) (2001), 3301-3307, I. Yasuhiro et al., Heterocycles, 45, 1997, 1151, J. Am. Chem. Soc. 105, 1983, 3214, J. Am. Chem. Soc. 124(47) (2002), 14017-14019, Chem. Commun. 1998, 659 or M. Falorni et al., Europ. J. Org. Chem. (8) (2000), 1669-1675.
• X can be halogen, in particular chlorine, bromine or iodine, or O—SO 2 —R m with R m having the meaning C 1 -C 4 -alkyl or aryl, which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl.
• the reaction is usually carried out at temperatures in the range from ⁇ 78° C. to the boiling point of the reaction mixture, preferably from ⁇ 50° C. to 65° C., particularly preferably from ⁇ 30° C. to 65° C.
• the reaction is carried out in a solvent, preferably in an inert organic solvent.
• Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C 5 -C 8 -alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-
• Suitable bases are inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, an aqueous solution of ammonia, alkali metal or alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides, such as lithium amide, for example lithium diisopropylamide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate, cesium carbonate and calcium carbonate and also alkali metal bicarbonates, such as sodium bicarbonate, organometallic compounds, in particular alkali
• the bases are generally employed in equimolar amounts. They can also be used in excess or even as solvent. In a preferred embodiment, the base is employed in an equimolar amount or an essentially equimolar amount. In a further preferred embodiment, the base used is sodium hydride.
• Suitable protective groups as group R 5a are in particular the radicals C(O)R 51 mentioned above, for example the acetyl radical.
• the introduction of these protective groups can be carried out analogously to known processes of protective group chemistry, for example by reaction with anhydrides of the formula (R 51 C(O)) 2 O, for example according to the method described in Green, Wuts, Protective Groups in Organic Synthesis, 3rd ed. 1999, John Wiley and Sons, p. 553.
• a protective group R 5a can be carried out analogously to known processes of protective group chemistry (see Green, Wuts, Protective Groups in Organic Synthesis, 3rd ed. 1999, John Wiley and Sons, p. 553).
• step iii) or in step Ha) can be carried out analogously to known processes for reducing C ⁇ C double bonds (see, for example, J. March, Advanced Organic Chemistry, 3rd ed. John Wiley and Sons 1985, pp. 690-700, and also Peptide Chemistry 17, 1980, pp. 59-64, Tetrahedron Lett. 46, 1979, pp. 4483-4486.
• the hydrogenation is frequently carried out by reaction with hydrogen in the presence of transition metal catalysts, for example catalysts comprising Pt, Pd, Rh or Ru as active metal species.
• transition metal catalysts for example catalysts comprising Pt, Pd, Rh or Ru as active metal species.
• Suitable are both heterogeneous catalysts, such as supported Pd or Pt catalysts, for example Pd on activated carbon, furthermore PtO 2 , and also homogeneous catalysts.
• stereoselective catalysts it is possible to carry out an enantioselective hydrogenation of the double bond (see Peptide Chemistry 17, 1980, pp. 59-64, Tetrahedron Lett. 46, 1979, pp. 4483-4486).
• the hydrogenation of II can be carried out either after the alkylation of II, i.e. in step iii), or prior to the alkylation of II, i.e. in step iia).
• a new radical R 5 different from hydrogen may be introduced by alkylation or by acylation.
• a subsequent alkylation or acylation for introducing the radical R 5 can be carried out using standard processes of organic chemistry, for example the methods indicated above for steps ii) and iiia).
• the preparation of the compound I in which R 11 is C 1 -C 4 -alkyl is expediently carried out by reacting the compound of the formula I in which R 11 is hydrogen with an alkylating agent R 11 —X in which R 11 is C 1 -C 4 -alkyl and X is a nucleophilically displaceable leaving group, for example halogen, in particular chlorine, bromine or iodine, or O—SO 2 —R m where R m has the meaning of C 1 -C 4 -alkyl or aryl which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl, in the presence of a base.
• R 11 has the meaning of C 1 -C 4 -alkyl or aryl which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl, in the presence of a
• the compounds of the formula II can be prepared, for example, by reacting a benzaldehyde of the formula III with a piperazine compound IV in the context of an aldol condensation, as illustrated in the scheme below:
• R 4a is a protective group, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 -C 4 -alkynyl.
• Suitable protective groups for the nitrogen atoms of the piperazine ring are in particular acyl groups, for example groups of the formula C(O)R 52 in which R 52 has one of the meanings given for R 51 and is in particular C 1 -C 4 -alkyl, for example methyl.
• the aldol condensation is typically carried out in the presence of suitable bases.
• suitable bases are those which are usually employed for aldol condensations. Preference is given to using an alkali metal or alkaline earth metal carbonate as base, for example sodium carbonate, potassium carbonate or cesium carbonate or mixtures thereof.
• the reaction is preferably carried out in an inert, preferably aprotic organic solvent.
• suitable solvents are in particular dichloromethane, dichloroethane, chlorbenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, and also dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide.
• Preferred solvents are in particular selected from the group consisting of dimethylformamide, N-methylpyrrolidone and dimethylacetamide.
• the temperatures required for the aldol condensation are generally in the range of from 0° C. to the boiling point of the solvent used and in particular in the range of from 10 to 80° C.
• radicals R 4a and R 5a in the compound IV represent an acyl group, for example a group of the formula R 52 C(O)—, in which R 52 has one of the meanings given for R 51 and is in particular C 1 -C 4 -alkyl, for example methyl.
• protective groups into the compound IV can be carried out analogously to known processes of protective group chemistry, for example by reacting the corresponding NH-free compound (the compound of the formula IV where R 4a , R 5a ⁇ H) with anhydrides of the formula (R 52 C(O)) 2 O, for example according to the method described in Green, Wuts, Protective Groups in Organic Synthesis, 3rd ed. 1999, John Wiley and Sons, p. 553.
• the removal of a protective group R 4a , R 5a can be carried out analogously to known processes of protective group chemistry.
• radicals R 4a and R 5a in the compound IV represent a protective group, for example an acyl group, these radicals are removed after the aldol condensation, which gives a compound of the formula II′,
• R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 have the meanings above for formula I.
• the protective groups are generally removed by hydrolysis, the radical R 4a frequently already being cleaved off under the conditions of an aldol condensation.
• the radical R 4 is then introduced by alkylation and, if appropriate, the radical R 5 is introduced by an alkylation or acylation.
• step ii) and step iiia The alkylation of the compound of the formula II′ for the introduction of the radicals R 4 and R 5 or R 5a can be carried out analogously to the methods given for step ii) and step iiia), for example according to the methods described in Heterocycles, 45, 1997, 1151, and Chem. Commun. 1998, 659.
• the piperazine compound of the formula II′ is reacted with a suitable alkylating agent, hereinbelow compound X 1 —R 4 and X 1 —R 5a or X 1 —R 5a .
• a suitable alkylating agent hereinbelow compound X 1 —R 4 and X 1 —R 5a or X 1 —R 5a .
• X 1 may be halogen or O—SO 2 —R m where R m has the meaning C 1 -C 4 -alkyl or aryl which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl.
• alkylating agents X 1 —R 4 , X 1 —R 5 and X 1 —R 5a , R 4 , R 5 and R 5a independently of one another are C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 -C 4 -alkynyl.
• reaction of the compound II with the alkylating agent(s) X 1 —R 4 , X 1 —R 5 and X 1 —R 5a is preferably carried in the presence of a base.
• a base With respect to temperatures, bases and solvents, what was said for step ii) and iiia) applies in an analogous manner.
• reaction of II′ with X 1 —R 4 and X 1 —R 5 or X 1 —R 5a can be carried out simultaneously or successively in any order. If the radicals R 4 , R 5 and R 6 are identical, the reaction of II′ with X—R 4 and X 1 —R 5 or X 1 —R 5a can be carried out at the same time as step ii) of the process according to the invention.
• R 5 in formula I is an acyl group
• this radical is introduced by an acylation before or after the hydrogenation of II.
• the compound I where R 5 ⁇ H is reacted with an acylating agent, hereinbelow compound X 2 —R 5 .
• R 5 is a radical C(O)R 51 in which R 51 has the meanings mentioned above.
• X 2 is generally halogen, for example chlorine, or a group O—C(O)—R 51 .
• the reaction can be carried out analogously to the reaction of II with the alkylating agents X 1 —R 4 or X 1 —R 5 .
• the compound obtained in the alkylation of compound II in step ii) can also be prepared analogously to the preparation of II by reaction of the benzaldehyde compound III with a compound IVa:
• R 1 , R 2 , R 3 , R 4a , R 5a , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings mentioned above, in particular one of the meanings mentioned as being preferred.
• Preferred radicals R 4a and R 5a in formula IVa are the acyl groups mentioned above of the formula R 52 C(O) in which R 52 has one of the meanings given for R 51 and is in particular C 1 -C 4 -alkyl, for example methyl.
• R 4a and/or R 5a in formula IVa are protective groups/is a protective group, for example acyl group of the formula R 52 C(O), the protective groups R 4a and/or R 5a will preferably be removed before the hydrogenation in step iii) of the process according to the invention. This gives a compound IIa in which R 4a and, if appropriate, R 5a , are hydrogen.
• This compound IIa in which R 4a is hydrogen is reacted with an alkylating agent of the formula R 4 —X 1 , preferably in the presence of a base before or after the hydrogenation.
• R 5a is hydrogen
• the compound IIa is reacted with, if appropriate, an alkylating agent of the formula R 5 —X 1 or an acylating agent R 5 —X 2 , preferably in the presence of a base.
• the aldehyde III is either commercially available or can be synthesized according to known processes for preparing aldehydes.
• the compounds of the formulae IV and IVa can be prepared by intramolecular cyclization of compounds of the general formula V and Va, respectively, analogously to other processes known from the literature, for example according to T. Kawasaki et al., Org. Lett. 2(19) (2000), 3027-3029, Igor L. Rodionov et al., Tetrahedron 58(42) (2002), 8515-8523 or A. L. Johnson et al., Tetrahedron 60 (2004), 961-965.
• R 4a , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings mentioned above.
• R 5b is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 -C 4 -alkynyl.
• R x is here, for example, C 1 -C 6 -alkyl, in particular methyl or ethyl, or phenyl-C 1 -C 6 -alkyl, for example benzyl.
• the cyclization of the compounds of the formula V or Va can be carried out in the presence of a base.
• the reaction is generally carried out at temperatures in the range of from 0° C. to the boiling point of the reaction mixture, preferably from 10° C. to 50° C., particularly preferably from 15° C. to 35° C.
• the reaction can be carried out in a solvent, preferably in an inert organic solvent.
• Suitable inert organic solvents include aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and mixtures of C 5 -C 8 -alkanes, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone, alcohols, such as methanol, ethanol, n-propanol, isopropanol
• Suitable bases are, for example, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, an aqueous solution of ammonia, alkali metal or alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal amides, such as lithium amide, for example lithium diisopropylamide, sodium amide and potassium amide, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate, cesium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, organometallic compounds, in particular alkali metal alkyls, such as methyllithium, butyllithium and phenyllithium, alkylmagnesium halides,
• the reaction is carried out in the presence of an aqueous solution of ammonia which may, for example, be of a strength of from 10 to 50% w/v.
• the cyclization is carried out in a mixture comprising n-butanol or a mixture of butanol isomers (for example, a mixture of n-butanol and 2-butanol and/or isobutanol) and N-methylmorpholine, preferably under reflux conditions.
• n-butanol or a mixture of butanol isomers for example, a mixture of n-butanol and 2-butanol and/or isobutanol
• N-methylmorpholine preferably under reflux conditions.
• the cyclization of V or Va can also be carried out with acid catalysis, in the presence of activating compounds or thermally.
• the reaction of V in the presence of an acid is usually carried out at temperatures in the range of from 10° C. to the boiling point of the reaction mixture, preferably from 50° C. to the boiling point, particularly preferably at the boiling point under reflux.
• the reaction is carried out in a solvent, preferably in an inert organic solvent.
• Suitable solvents are, in principle, those which can also be used for the basic cyclization, in particular alcohols.
• the reaction is carried out in n-butanol or a mixture of different butanol isomers (for example a mixture of n-butanol and 2-butanol and/or isobutanol).
• Suitable acids for the cyclization of V or Va are, in principle, both Brönstedt and Lewis acids.
• Use may be made in particular of inorganic acids, for example hydrohalic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, inorganic oxoacids, such as sulfuric acid and perchloric acid, furthermore of inorganic Lewis acids, such as borin trifluoride, aluminum trichloride, iron(III) chloride, tin(IV) chloride, titanium(IV) chloride and zinc(II) chloride, and also of organic acids, for example carboxylic acids and hydroxycarboxylic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, citric acid and trifluoroacetic acid, and also organic sulfonic acids, such as toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and the like.
• inorganic acids for example
• the reaction is carried out in the presence of organic acids, for example in the presence of carboxylic acids, such as formic acid, acetic acid or trifluoroacetic acid or a mixture of these acids. Preferably, only one of these acids is used. In a preferred embodiment, the reaction is carried out in acetic acid.
• the acidic cyclization is carried out in a mixture comprising n-butanol or a butanol isomer mixture (for example a mixture of n-butanol and 2-butanol and/or isobutanol), N-methylmorpholine and acetic acid, preferably under reflux conditions.
• n-butanol or a butanol isomer mixture for example a mixture of n-butanol and 2-butanol and/or isobutanol
• N-methylmorpholine for example a mixture of n-butanol and 2-butanol and/or isobutanol
• acetic acid preferably under reflux conditions.
• the conversion of V or Va is carried out by treatment with an activating agent in the presence of a base.
• R x is hydrogen.
• An example of a suitable activating agent is di-(N-succinimidinyl) carbonate.
• Suitable activating agents are furthermore polystyrene- or non-polystyrene-supported di-cyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDAC), carbonyldiimidazole (CDI), chloroformic esters, such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate or allyl chloroformate, pivaloyl chloride, polyphosphoric acid, propanephosphonic anhydride, bis(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOPCl) or sulfonyl chlorides, such as methanesulfonyl chloride, toluenesulfonyl chloride or benzenesulfony
• Suitable bases are the compounds cited for the basic cyclization.
• the base used is triethylamine or N-ethyldiisopropylamine or mixtures thereof, particularly preferably N-ethyldiisopropylamine.
• the conversion of V or Va is carried out exclusively by heating the reaction mixture (thermal cyclization).
• the reaction is usually carried out at temperatures in the range of from 10° C. to the boiling point of the reaction mixture, preferably from 50° C. to the boiling point of the reaction mixture, particularly preferably at the boiling point of the reaction mixture under reflux.
• the reaction is generally carried out in a solvent, preferably in an inert organic solvent.
• suitable solvents are those solvents which can be used for the basic cyclization. Preference is given to polar aprotic solvents, for example dimethyl sulfoxide or dimethylformamide or mixtures thereof. In a preferred embodiment, the reaction is carried out in dimethyl sulfoxide.
• the piperazine nitrogens can then, to introduce the radicals R 4a or R 5a , be alkylated using an alkylating agent R 4a —X 1 or R 5a —X 1 or be provided with a protective group by reaction with an acylating agent R 4a —X 2 or R 5a —X 2 .
• R 4a , R 5a , X 1 and X 2 have the meanings given above.
• the compounds of the formula V or Va can be prepared by the scheme shown below analogously to processes from the literature, for example according to Wilford L. Mendelson et al., Int. J. Peptide & Protein Research 35(3), (1990), 249-57, Glenn L. Stahl et al., J. Org. Chem. 43(11), (1978), 2285-6 or A. K. Ghosh et al., Org. Lett. 3(4), (2001), 635-638.
• the variables R x , R 4a , R 5b , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings given for formula V.
• the synthesis comprises, in a first step, the coupling of glycine ester compounds of the formula VII with Boc-protected phenylalanine compounds VIII or VIIIa in the presence of an activating agent. Instead of Boc, it is also possible to use another amino-protective group.
• the reaction of a compound of the formula VII with a compound of the formula VIII or VIIIa is usually carried out at temperatures in the range of from ⁇ 30° C. to the boiling point of the reaction mixture, preferably of from 0° C. to 50° C., particularly preferably of from 20° C. to 35° C.
• the reaction can be carried out in a solvent, preferably in an inert organic solvent.
• activating agents are condensing agents, such as, for example, polystyrene- or non-polystyrene-supported dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, carbonyldiimidazole (CDI), 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDAC), chloroformic esters, such as methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate or allyl chloroformate, pivaloyl chloride, polyphosphoric acid, propanephosphonic anhydride, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (BOPCl) or sulfonyl chlorides, such as methane-sulfonyl chloride, to
• the reaction of VII with VIII or VIIIa is preferably carried out in the presence of a base.
• Suitable bases are the compounds listed for the cyclization of the dipeptide V to the piperazine IV.
• the base used is triethylamine or N-ethyldiisopropylamine or a mixture thereof, particularly preferably N-ethyldiisopropylamine.
• the deprotection of the compound VI or VIa to give the compound V or Va can be carried out by customary processes, such as, for example, according to Glenn L. Stahl et al., J. Org. Chem. 43(11), (1978), 2285-6 or A. K. Ghosh et al., Org. Lett. 3(4), (2001), 635-638.
• the deprotection is typically carried out by treatment with an acid. Suitable acids are both Brönstedt acids and Lewis acids, preferably organic carboxylic acids, for example formic acid, acetic acid or trifluoroacetic acid or mixtures thereof. In a preferred embodiment, the reaction is carried out in the presence of trifluoroacetic acid.
• the reaction is usually carried out at temperatures in the range of from ⁇ 30° C. to the boiling point of the reaction mixture, preferably from 0° C. to 50° C., particularly preferably from 20° C. to 35° C.
• the reaction can be carried out in a solvent, preferably in an inert organic solvent.
• Suitable solvents are, in principle, the solvents mentioned above in connection with the basic cyclization of V to IV, in particular tetrahydrofuran or dichloromethane or mixtures thereof. In a preferred embodiment, the reaction is carried out in dichloromethane.
• the compounds IV and IVa can also be prepared by intermolecular cyclization of a glycine ester derivative VIIa with a phenylalanine compound VIIIb or VIIIc according to the schemes below:
• R x , R 6 , R 7 , R 8 , R 9 and R 10 have the meanings given above.
• R y is alkyl, for example methyl or ethyl.
• the intermolecular cyclization can be effected, for example, by a base, for example ammonia.
• the compounds VIIa and/or VIIIb or VIIIc can also be employed in the form of their acid addition salts, for example as hydrochlorides.
• the preparation of the compounds I comprises
• R 5a has preferably one of the meanings given for R 5 different from hydrogen.
• the variable X has preferably one of the following meanings: halogen, in particular chlorine, bromine or iodine, or O—SO 2 —R m where R m has the meaning of C 1 -C 4 -alkyl or aryl which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl.
• Suitable protective groups for the nitrogen atoms of the piperazine rings in IX are in particular the radicals C(O)R 52 mentioned above, for example the acetyl radical.
• reaction of the compound I ⁇ with the compound X in step ii) can be carried out analogously to the method described in process A, step iv) or, for example, according to the method described in J. Am. Chem. Soc. 105, 1983, 3214.
• step ii) can likewise be carried out in the manner described above for the hydrogenation of compound II or IIa.
• the compounds IX can be provided, for example, by reacting the compound X 1 with a benzaldehyde compound XII, as illustrated in the scheme below.
• R 1 , R 2 , R 3 , R 5a and R 6 have the meanings mentioned above.
• R 4a has one of the meanings given above or is a protective group. Suitable protective groups for the nitrogen atoms of the piperazine ring in X 1 are in particular the radicals C(O)R 51 mentioned above, for example the acetyl radical.
• R 4a and R 5a are in particular one of the radicals C(O)R 52 mentioned above, for example acetyl radicals.
• reaction of X 1 with XII can be carried out under the conditions of an aldol condensation, as already described for the reaction of III with IV or IVa.
• aldol condensations can be carried out analogously to the processes described in J. Org. Chem. 2000, 65 (24), 8402-8405, Synlett 2006, 677, J. Heterocycl. Chem. 1988, 25, 591, which are hereby incorporated herein in their entirety.
• the reaction is generally carried out in the presence of a base.
• the base used is preferably an alkali metal or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate or cesium carbonate, or mixtures thereof.
• the reaction is preferably carried out in an inert, preferably aprotic organic solvent.
• suitable solvents are in particular dichloromethane, dichloroethane, chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles, such as acetonitrile and propionitrile, and also dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone and dimethylacetamide.
• ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran
• nitriles such as acetonitrile and propionitrile
• dimethyl sulfoxide dimethylformamide
• N-methylpyrrolidone dimethylacetamide
• the compounds reacted are preferably those compounds XI in which R 4a and R 5a are a protective group and in particular an acyl radical R 52 C(O)—(R 52 ⁇ C 1 -C 4 -alkyl), for example an acetyl radical. Accordingly, the condensation reaction is generally followed by a removal of the protective groups.
• the removal of a protective group R 4a , R 5a can be carried out analogously to known processes of protective group chemistry, for example by the method described in Green, Wuts, Protective Groups in Organic Synthesis, 3rd ed. 1999, John Wiley and Sons, p. 553. This results in compounds of the formula IX in which R 4a and R 5a are hydrogen.
• a subsequent alkylation for introducing the radicals R 4 and/or R 5 can be carried out by the method given above in process A for the alkylation of II, for example according to the methods described in Heterocycles, 45, 1997, 1151, and Chem. Commun. 1998, 659.
• the compounds XI are known. Their preparation can be carried out analogously to the preparation of the compounds V described above, according to the scheme shown below:
• R 4a , R 5a and R 6 have the meanings mentioned above.
• R x is preferably C 1 -C 4 -alkyl or benzyl.
• Boc is a tert-butoxycarbonyl radical.
• R 4a and R 5a are a protective group, for example a radical C(O)R 51
• these protective groups can be introduced analogously to known processes of protective group chemistry, for example by reaction with anhydrides of the formula (R 51 C(O)) 2 O, for example by the method described in Green, Wuts, Protective Groups in Organic Synthesis, 3rd ed. 1999, John Wiley and Sons, p. 553.
• the preparation of the compound I is carried out by cyclization of corresponding dipeptide precursors of the formula XIII, for example analogously to the method described by T. Kawasaki et al., Org. Lett. 2(19) (2000), 3027-3029, Igor L. Rodionov et al., Tetrahedron 58(42) (2002), 8515-8523 or A. L. Johnson et al., Tetrahedron 60 (2004), 961-965.
• the cyclization of dipeptides of the formula XIII to the compounds according to the invention is also referred to as process C and is illustrated in the scheme below.
• R 4c is hydrogen or R 4 .
• R 5c is hydrogen, C 1 -C 4 -alkyl, C 3 -C 4 -alkenyl or C 3 -C 4 -alkynyl.
• the group OR x is a suitable leaving group attached via oxygen.
• R x is, for example, hydrogen, C 1 -C 6 -alkyl, in particular methyl or ethyl, or phenyl-C 1 -C 6 -alkyl, for example benzyl.
• Dipeptides of the general formula XIII are novel and also form part of the subject matter of the present invention.
• the cyclization can be carried out, for example, by reacting a dipeptide of the formula XIII either in the presence of acid or base (acidic or basic cyclization) or by heating the reaction mixture (thermal cyclization).
• reaction conditions reference is made to what was said for the cyclization of V to compound IV.
• R 4c and R 5c in formula XIII are hydrogen.
• an alkylation or acylation is carried out to introduce the radicals R 4 and R 5 , respectively.
• dipeptide compounds XIII can be carried out analogously to the preparation of the compound V.
• the preparation is illustrated in the scheme below:
• the compounds of the formula I where R 5 ⁇ H can also be prepared by reacting a piperazine compound of the formula I in which R 5 is hydrogen with an alkylating agent or acylating agent which contains the radical R 5 different from hydrogen. Such reactions can be carried out analogously to the methods discussed in connection with process A steps ii), iiia) and iv).
• X 1 can be halogen or O—SO 2 —R m where R m has the meaning C 1 -C 4 -alkyl or aryl which are optionally substituted by halogen, C 1 -C 4 -alkyl or halo-C 1 -C 4 -alkyl.
• acylating agents X 2 —R 5 X 2 can be halogen, in particular Cl.
• R 5 is a radical (CO)R 51 .
• the reaction is usually carried out at temperatures in the range of from ⁇ 78° C. to the boiling point of the reaction mixture, preferably from ⁇ 50° C. to 65° C., particularly preferably from ⁇ 30° C. to 65° C.
• the reaction is carried out in a solvent, preferably in an inert organic solvent.
• Suitable solvents are the compounds mentioned for the cyclization of the dipeptide V to the piperazine IV, inter alia toluene, dichloromethane, tetrahydrofuran or dimethylformamide or mixtures thereof.
• the compound I where R 5 ⁇ H is reacted with the alkylating or acylating agent in the presence of a base.
• Suitable bases are the compounds mentioned for the cyclization of the dipeptide V to the piperazine IV.
• the bases are generally employed in equimolar amounts. They can also be used in excess or even as solvent.
• the base is added in an equimolar amount or in an essentially equimolar amount.
• the base used is sodium hydride.
• the alkylation or acylation of the group NR 5 in which R 5 is H can also be carried out using the precursors.
• compounds II, IV, V, VI, VIII in which R 5a or R 5b is H can be N-alkylated or N-acylated as described above.
• the compounds of the formula I can furthermore be modified at group R 1 .
• R 1 is CN
• optionally substituted phenyl or an optionally substituted heterocyclic radical can be prepared from compounds I in which R 1 is halogen, such as chlorine, bromine or iodine, by conversion of the substituent R 1 , for example analogously to the methods described by J. Tsuji, Top. Organomet. Chem. (14) (2005), 332 pp., J. Tsuji, Organic Synthesis with Palladium Compounds, (1980), 207 pp., Tetrahedron Lett. 42, 2001, p. 7473 or Org. Lett. 5, 2003, 1785.
• a piperazine compound of the formula I which, as substituent R 1 , has a halogen atom, such as chlorine, bromine or iodine, can be converted by reaction with a coupling partner which contains a group R 1 (compound R 1 —X 3 ) into another piperazine derivative of the formula I.
• a coupling partner which contains a group R 1 (compound R 1 —X 3 ) into another piperazine derivative of the formula I.
• the reaction is usually carried out in the presence of a catalyst, preferably in the presence of a transition metal catalyst. In general, the reaction is carried out in the presence of a base.
• Suitable coupling reagents X 3 —R 1 are in particular those compounds in which X 3 , if R 1 is phenyl or a heterocyclic radical (heterocyclyl), denotes one of the following groups:
• This reaction is usually carried out at temperatures in the range from ⁇ 78° C. to the boiling point of the reaction mixture, preferably from ⁇ 30° C. to 65° C., particularly preferably at temperatures from 30° C. to 65° C.
• the reaction is carried out in an inert organic solvent in the presence of a base.
• Suitable solvents are the compounds mentioned in connection with the cyclization of the dipeptide IV to the piperazine V.
• use is made of tetrahydrofuran with a catalytic amount of water; in another embodiment, only tetrahydrofuran is used.
• Suitable bases are the compounds mentioned for the cyclization of the dipeptide IV to the piperazine V.
• the bases are generally employed in equimolar amounts. They can also be employed in excess or even as solvent.
• the base is added in an equimolar amount.
• the base used is triethylamine or cesium carbonate, particularly preferably cesium carbonate.
• Suitable catalysts for the process according to the invention are, in principle, compounds of the transition metals Ni, Fe, Pd, Pt, Zr or Cu. It is possible to use organic or inorganic compounds. Pd(PPh 3 ) 2 Cl 2 , Pd(OAc) 2 , PdCl 2 or Na 2 PdCl 4 may be mentioned by way of example.
• Ph is phenyl; Ac is Acetyl.
• the different catalysts can be employed either individually or else as mixtures.
• Pd(PPh 3 ) 2 Cl 2 is used.
• the compound I in which R 1 is chlorine, bromine or iodine can also be reacted with copper cyanide, analogously to known processes (see, for example, Organikum, 21. edition, 2001, Wiley, p. 404, Tetrahedron Lett. 42, 2001, p. 7473 or Org. Lett. 5, 2003, 1785 and the literature cited therein).
• reaction is carried out at temperatures in the range of from 100° C. to the boiling point of the reaction mixture, preferably at from 100° C. to 250° C.
• the reaction is carried out in an inert organic solvent.
• Suitable solvents are in particular aprotic polar solvents, for example dimethylformamide, N-methylpyrrolidone, N,N′-dimethylimidazolidin-2-one and dimethylacetamide.
• the conversion of group R 1 can also be carried out on the precursors of the compound I.
• R 1 is a halogen atom such as chlorine, bromine or iodine
• compounds II in which R 1 is a halogen atom such as chlorine, bromine or iodine can be subjected to the reaction described above.
• the alkylation or acylation of the group NR 4a , NR 5a in which R 4a or R 5a is H can also be carried out using the precursors,
• compounds II, IV, V, VI, VIII in which R 5a or R 5b is H can be N-alkylated or N-acylated as described above.
• the compounds I and their agriculturally useful salts are suitable, both in the form of isomer mixtures and in the form of the pure isomers, as herbicides. They are suitable as such or as an appropriately formulated composition.
• the herbicidal compositions comprising the compound I or Ia control vegetation on non-crop areas very efficiently, especially at high rates of application. They act against broad-leaved weeds and grass weeds in crops such as wheat, rice, maize, soya and cotton without causing any significant damage to the crop plants. This effect is mainly observed at low rates of application.
• the compounds I or Ia, or compositions comprising them can additionally be employed in a further number of crop plants for eliminating undesirable plants.
• suitable crops are the following:
• Preferred crops are the following: Arachis hypogaea, Beta vulgaris spec. altissima, Brassica napus var. napus, Brassica oleracea, Citrus limon, Citrus sinensis, Coffea arabica ( Coffea canephora, Coffea liberica ), Cynodon dactylon, Glycine max, Gossypium hirsutum , ( Gossypium arboreum, Gossypium herbaceum, Gossypium vitifolium ), Helianthus annuus, Hordeum vulgare, Juglans regia, Lens culinaris, Linum usitatissimum, Lycopersicon lycopersicum, Malus spec., Medicago sativa, Nicotiana tabacum ( N.
• the compounds of the formula I may also be used in crops which tolerate the action of herbicides owing to breeding, including genetic engineering methods.
• the compounds of the formula I can also be used in crops which tolerate insects or fungal attack as the result of breeding, including genetic engineering methods.
• the compounds of the formula I are also suitable for the defoliation and/or desiccation of plant parts, for which crop plants such as cotton, potato, oilseed rape, sunflower, soybean or field beans, in particular cotton, are suitable.
• crop plants such as cotton, potato, oilseed rape, sunflower, soybean or field beans, in particular cotton
• compositions for the desiccation and/or defoliation of plants processes for preparing these compositions and methods for desiccating and/or defoliating plants using the compounds of the formula I.
• the compounds of the formula I are particularly suitable for desiccating the above-ground parts of crop plants such as potato, oilseed rape, sunflower and soybean, but also cereals. This makes possible the fully mechanical harvesting of these important crop plants.
• Also of economic interest is to facilitate harvesting, which is made possible by concentrating within a certain period of time the dehiscence, or reduction of adhesion to the tree, in citrus fruit, olives and other species and varieties of pernicious fruit, stone fruit and nuts.
• the same mechanism i.e. the promotion of the development of abscission tissue between fruit part or leaf part and shoot part of the plants is also essential for the controlled defoliation of useful plants, in particular cotton.
• the compounds I, or the herbicidal compositions comprising the compounds I can be used, for example, in the form of ready-to-spray aqueous solutions, powders, suspensions, also highly concentrated aqueous, oily or other suspensions or dispersions, emulsions, oil dispersions, pastes, dusts, materials for broadcasting, or granules, by means of spraying, atomizing, dusting, spreading, watering or treatment of the seed or mixing with the seed.
• the use forms depend on the intended purpose; in any case, they should ensure the finest possible distribution of the active ingredients according to the invention.
• the herbicidal compositions comprise a herbicidally effective amount of at least one compound of the formula I or an agriculturally useful salt of I, and auxiliaries which are customary for the formulation of crop protection agents.
• auxiliaries customary for the formulation of crop protection agents are inert auxiliaries, solid carriers, surfactants (such as dispersants, protective colloids, emulsifiers, wetting agents and tackifiers), organic and inorganic thickeners, bactericides, antifreeze agents, antifoams, optionally colorants and, for seed formulations, adhesives.
• surfactants such as dispersants, protective colloids, emulsifiers, wetting agents and tackifiers
• organic and inorganic thickeners such as bactericides, antifreeze agents, antifoams, optionally colorants and, for seed formulations, adhesives.
• thickeners i.e. compounds which impart to the formulation modified flow properties, i.e. high viscosity in the state of rest and low viscosity in motion
• thickeners are polysaccharides, such as xanthan gum (Kelzan® from Kelco), Rhodopol® 23 (Rhone Poulenc) or Veegum® (from R. T. Vanderbilt), and also organic and inorganic sheet minerals, such as Attaclay® (from Engelhardt).
• antifoams examples include silicone emulsions (such as, for example, Silikon® SRE, Wacker or Rhodorsil® from Rhodia), long-chain alcohols, fatty acids, salts of fatty acids, organofluorine compounds and mixtures thereof.
• Bactericides can be added for stabilizing the aqueous herbicidal formulations.
• bactericides are bactericides based on dichlorophen and benzyl alcohol hemiformal (Proxel® from ICI or Acticide® RS from Thor Chemie and Kathon® MK from Rohm & Haas), and also isothiazolinone derivates, such as alkylisothiazolinones and benzisothiazolinones (Acticide MBS from Thor Chemie).
• antifreeze agents are ethylene glycol, propylene glycol, urea or glycerol.
• colorants are both sparingly water-soluble pigments and water-soluble dyes. Examples which may be mentioned are the dyes known under the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1, and also pigment blue 15:4, pigment blue 15:3, pigment blue 15:2, pigment blue 15:1, pigment blue 80, pigment yellow 1, pigment yellow 13, pigment red 112, pigment red 48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigment orange 43, pigment orange 34, pigment orange 5, pigment green 36, pigment green 7, pigment white 6, pigment brown 25, basic violet 10, basic violet 49, acid red 51, acid red 52, acid red 14, acid blue 9, acid yellow 23, basic red 10, basic red 108.
• adhesives are polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose.
• Suitable inert auxiliaries are, for example, the following:
• mineral oil fractions of medium to high boiling point such as kerosene and diesel oil, furthermore coal tar oils and oils of vegetable or animal origin, aliphatic, cyclic and aromatic hydrocarbons, for example paraffin, tetrahydronaphthalene, alkylated naphthalenes and their derivatives, alkylated benzenes and their derivatives, alcohols such as methanol, ethanol, propanol, butanol and cyclohexanol, ketones such as cyclohexanone or strongly polar solvents, for example amines such as N-methylpyrrolidone, and water.
• paraffin tetrahydronaphthalene
• alkylated naphthalenes and their derivatives alkylated benzenes and their derivatives
• alcohols such as methanol, ethanol, propanol, butanol and cyclohexanol
• ketones such as cyclohexanone or strongly polar
• Solid carriers are mineral earths such as silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate and magnesium oxide, ground synthetic materials, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate and ureas, and products of vegetable origin, such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders, or other solid carriers.
• mineral earths such as silicas, silica gels, silicates, talc, kaolin, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate and magnesium oxide, ground synthetic materials, fertilizers such as ammonium sulfate, ammonium phosphate, ammonium nitrate and urea
• Suitable surfactants are the alkali metal salts, alkaline earth metal salts and ammonium salts of aromatic sulfonic acids, for example lignosulfonic acids (e.g.
• methylcellulose methylcellulose
• hydrophobically modified starches polyvinyl alcohol (Mowiol types Clariant), polycarboxylates (BASF AG, Sokalan types), polyalkoxylates, polyvinylamine (BASF AG, Lupamine types), polyethyleneimine (BASF AG, Lupasol types), polyvinylpyrrolidone and copolymers thereof.
• Powders, materials for broadcasting and dusts can be prepared by mixing or grinding the active ingredients together with a solid carrier.
• Granules for example coated granules, impregnated granules and homogeneous granules, can be prepared by binding the active ingredients to solid carriers.
• Aqueous use forms can be prepared from emulsion concentrates, suspensions, pastes, wettable powders or water-dispersible granules by adding water.
• the compounds of the formula I or Ia can be homogenized in water by means of a wetting agent, tackifier, dispersant or emulsifier.
• a wetting agent e.g., tackifier, dispersant or emulsifier
• concentrates comprising active compound, wetting agent, tackifier, dispersant or emulsifier and, if desired, solvent or oil, which are suitable for dilution with water.
• the concentrations of the compounds of the formula I in the ready-to-use preparations can be varied within wide ranges.
• the formulations comprise approximately from 0.001 to 98% by weight, preferably 0.01 to 95% by weight of at least one active ingredient.
• the active ingredients are employed in a purity of from 90% to 100%, preferably 95% to 100% (according to NMR spectrum).
• the compounds I of the invention can for example be formulated as follows:
• active compound 10 parts by weight of active compound are dissolved in 90 parts by weight of water or a water-soluble solvent. As an alternative, wetters or other adjuvants are added. The active compound dissolves upon dilution with water. This gives a formulation with an active compound content of 10% by weight.
• active compound 20 parts by weight of active compound are dissolved in 70 parts by weight of cyclohexanone with addition of 10 parts by weight of a dispersant, for example polyvinylpyrrolidone. Dilution with water gives a dispersion.
• a dispersant for example polyvinylpyrrolidone.
• the active compound content is 20% by weight.
• active compound 15 parts by weight of active compound are dissolved in 75 parts by weight of an organic solvent (eg. alkylaromatics) with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). Dilution with water gives an emulsion.
• the formulation has an active compound content of 15% by weight.
• active compound 25 parts by weight of active compound are dissolved in 35 parts by weight of an organic solvent (eg. alkylaromatics) with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight).
• organic solvent eg. alkylaromatics
• calcium dodecylbenzenesulfonate and castor oil ethoxylate in each case 5 parts by weight.
• This mixture is introduced into 30 parts by weight of water by means of an emulsifier (Ultraturrax) and made into a homogeneous emulsion. Dilution with water gives an emulsion.
• the formulation has an active compound content of 25% by weight.
• active compound 20 parts by weight of active compound are comminuted with addition of 10 parts by weight of dispersants and wetters and 70 parts by weight of water or an organic solvent to give a fine active compound suspension. Dilution with water gives a stable suspension of the active compound.
• the active compound content in the formulation is 20% by weight.
• active compound 50 parts by weight of active compound are ground finely with addition of 50 parts by weight of dispersants and wetters and made into water-dispersible or water-soluble granules by means of technical appliances (for example extrusion, spray tower, fluidized bed). Dilution with water gives a stable dispersion or solution of the active compound.
• the formulation has an active compound content of 50% by weight.
• active compound 75 parts by weight of active compound are ground in a rotor-stator mill with addition of 25 parts by weight of dispersants, wetters and silica gel. Dilution with water gives a stable dispersion or solution of the active compound.
• the active compound content of the formulation is 75% by weight.
• active compound 0.5 parts by weight are ground finely and associated with 99.5 parts by weight of carriers. Current methods here are extrusion, spray-drying or the fluidized bed. This gives granules to be applied undiluted with an active compound content of 0.5% by weight.
• the compounds of the formula I or the herbicidal compositions comprising them can be applied pre- or post-emergence, or together with the seed of a crop plant. It is also possible to apply the herbicidal composition or active compounds by applying seed, pretreated with the herbicidal compositions or active compounds, of a crop plant. If the active ingredients are less well tolerated by certain crop plants, application techniques may be used in which the herbicidal compositions are sprayed, with the aid of the spraying equipment, in such a way that as far as possible they do not come into contact with the leaves of the sensitive crop plants, while the active ingredients reach the leaves of undesirable plants growing underneath, or the bare soil surface (post-directed, lay-by).
• the compounds of the formula I or the herbicidal compositions can be applied by treating seed.
• the treatment of seeds comprises essentially all procedures familiar to the person skilled in the art (seed dressing, seed coating, seed dusting, seed soaking, seed film coating, seed multilayer coating, seed encrusting, seed dripping and seed pelleting) based on the compounds of the formula I according to the invention or the compositions prepared therefrom.
• the herbicidal compositions can be applied diluted or undiluted.
• seed comprises seed of all types, such as, for example, corns, seeds, fruits, tubers, seedlings and similar forms.
• seed describes corns and seeds.
• the seed used can be seed of the useful plants mentioned above, but also the seed of transgenic plants or plants obtained by customary breeding methods.
• the rates of application of the active compound are from 0.001 to 3.0, preferably 0.01 to 1.0, kg/ha of active substance (a.s.), depending on the control target, the season, the target plants and the growth stage.
• the compounds I are generally employed in amounts of from 0.001 to 10 kg per 100 kg of seed.
• the compounds of the formula I may be mixed with a large number of representatives of other herbicidal or growth-regulating active ingredient groups and then applied concomitantly.
• Suitable components for mixtures are, for example, 1,2,4-thiadiazoles, 1,3,4-thiadiazoles, amides, aminophosphoric acid and its derivatives, aminotriazoles, anilides, (het)aryloxyalkanoic acids and their derivatives, benzoic acid and its derivatives, benzothiadiazinones, 2-aroyl-1,3-cyclohexanediones, 2-hetaroyl-1,3-cyclohexane-diones, hetaryl aryl ketones, benzylisoxazolidinones, meta-CF 3 -phenyl derivatives, carbamates, quinolinecarboxylic acid and its derivatives, chloroacetanilides, cyclohexenone oxime ether
• Safeners are chemical compounds which prevent or reduce damage on useful plants without having a major impact on the herbicidal action of the compounds of the formula I towards unwanted plants. They can be applied either before sowings (e.g. on seed treatments, shoots or seedlings) or in the pre-emergence application or post-emergence application of the useful plant.
• the safeners and the compounds of the formula I can be applied simultaneously or in succession. Suitable safener are e.g.
• HPLC-MS high performance liquid chromatography coupled with mass spectrometry
• HPLC column RP-18 column (Chromolith Speed ROD from Merck KgaA, Germany), 50 ⁇ 4,6 mm
• mobile phase acetonitrile+0.1% trifluoroacetic acid (TFA)/water+0.1% TFA, gradient from 5:95 to 100:0 over 5 minutes at 40° C., flow rate 1.8 ml/min;
• ethyldiisopropylamine (259 g, 2.0 mol), N-tert-butoxycarbonyl-L-phenyl-alanine (212 g, 0.8 mol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDAC, 230 g, 1.2 mol) were added to a solution of glycine methyl ester hydrochloride (100 g, 0.8 mol) in tetrahydrofuran (THF, 1000 ml). The reaction mixture was then stirred at room temperature for 24 h.
• THF tetrahydrofuran
• the reaction mixture obtained was freed under reduced pressure from volatile components, and the residue obtained in this manner was taken up in water (1000 ml).
• the aqueous phase was extracted repeatedly with CH 2 Cl 2 .
• the organic phases obtained in this manner were combined, washed with water, dried over Na 2 SO 4 , filtered and freed from the solvent under reduced pressure.
• Methyl (2-tert-butoxycarbonylamino-3-phenylpropionylamino)acetate was obtained as a yellow oil in an amount of 300 g.
• the crude product obtained was reacted further without further purification.
• Ethyl glycinate hydrochloride (37 g, 0.27 mol) was dissolved in a solution of K 2 CO 3 (74.4 g, 0.54 mol) in water (186 ml). The solution was stirred for 15 min and then extracted with dichloromethane (10*150 ml). The organic phases obtained in this manner were combined, dried over MgSO 4 and freed from solvent under reduced pressure (500 mbar) (yield ⁇ 50%). The residue (9.5 g, 0.092 mol) was, together with benzophenone (14.03 g, 0.077 mol) dissolved in xylene (76 ml). After addition of a few drops of BF 3 *Et 20 , the reaction mixture was stirred under reflux conditions on a water separator for 5 h. After cooling of the reaction mixture to room temperature, the solvent was removed under reduced pressure.
• Aqueous sodium hydroxide solution NaOH (10% strength, 40 ml) was added to a solution of ethyl N-(diphenylmethylene)glycinate (5 g, 18.7 mmol; from Example 2.1), 2-cyanobenzyl bromide (4.1 g, 20.7 mmol) and tetrabutylammonium sulfate (320 m, 0.9 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature overnight. The phases were separated, and the aqueous phase was then extracted with dichloromethane (2 times 50 ml).
• Aqueous sodium hydroxide solution (1M, 170 ml) was added to a suspension of ⁇ -methylphenylalanine (20 g, 0.11 mol) in dioxane/water (2:1, 300 ml).
• a solution of di-tert-butyl dicarbonate 29.2 g, 0.134 mol
• dioxane 50 ml
• the reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS analysis. In each case half an equivalent of di-tert-butyl dicarbonate was added until no more starting material could be detected.
• the pH was adjusted to 9 using aqueous sodium hydroxide solution NaOH (1M). Using 10% strength aqueous hydrochloric acid, the reaction mixture was then adjusted to a pH of 2 and extracted with ethyl acetate. The organic phases obtained were combined, washed with water, dried over MgSO 4 , filtered and freed from the solvent under reduced pressure. The N-(tert-butoxycarbonyl)- ⁇ -methylphenylalanine obtained as a residue in a yield of 88% can be used without further purification for the next step.
• Ethyl ⁇ -(2-cyanophenyl)alaninate hydrochloride (8.6 g, 33.8 mmol) was then added a little at a time, followed by diisopropylethylamine (DIPEA, 8.7 g, 67.6 mmol).
• DIPEA diisopropylethylamine
• the reaction mixture was stirred at 45° C. overnight and then under reflux conditions for 2 h.
• the reaction mixture was put onto aqueous 5% strength citric acid and then extracted with ethyl acetate.
• the organic phases obtained were combined, washed with saturated aqueous NaHCO 3 solution, dried over MgSO 4 , filtered and freed from the solvent under reduced pressure.
• Trifluoroacetic acid (TFA, 8.20 g, 71.9 mmol) was added to a solution of (N-Boc- ⁇ -CH 3 -Phe)-(o-CN-Phe)-OC 2 H 5 (4.1 g, 8.5 mmol) in dichloromethane (14 ml). The reaction mixture was stirred at room temperature for 2 h and then freed from volatile components under reduced pressure. The residue was taken up in chloroform. The reaction mixture was washed with saturated aqueous Na 2 CO 3 solution. The organic phase was dried over MgSO 4 , filtered and freed from the solvent under reduced pressure.
• TFA Trifluoroacetic acid
• the culture containers used were plastic flowerpots containing loamy sand with approximately 3.0% of humus as the substrate.
• the seeds of the test plants were sown separately for each species.
• the active ingredients which had been suspended or emulsified in water, were applied directly after sowing by means of finely distributing nozzles.
• the containers were irrigated gently to promote germination and growth and subsequently covered with transparent plastic hoods until the plants had rooted. This cover caused uniform germination of the test plants, unless this has been impaired by the active ingredients.
• test plants were first grown to a height of 3 to 15 cm, depending on the plant habit, and only then treated with the active ingredients which had been suspended or emulsified in water.
• the test plants were either sown directly and grown in the same containers, or they were first grown separately as seedlings and transplanted into the test containers a few days prior to treatment.
• the plants were kept at 10-25° C. or 20-35° C.
• the test period extended over 2 to 4 weeks. During this time, the plants were tended, and their response to the individual treatments was evaluated.
• Evaluation was carried out using a scale from 0 to 100. 100 means no emergence of the plants, or complete destruction of at least the aerial moieties, and 0 means no damage, or normal course of growth. A good herbicidal activity is given at values of at least 70 and a very good herbicidal activity is given at values of at least 85.
• Bayer Code Scientific name Common name AMARE Amaranthus retoflexus redroot pigweed ALOMY Alopecurus myosuroides black grass APESV Apera spica - venti windgrass CHEAL Chenopodium album common lambsquarters ECHCG Echinochloa crus - galli barnyard grass SETFA Setaria faberi giant foxtail SETVI Setaria viridis green foxtail
• the compounds according to the invention applied by the pre-emergence method, showed very good herbicidal activity.
• Example 1 main isomer 1
• the compound of Example 1 (main isomer 1) applied by the pre-emergence method, showed very good herbicidal activity against AMARE, ALOMY, APESV, ECHCG and SETFA.
• Example 2 the compound of Example 1 (minor isomer 2), applied by the pre-emergence method, showed very good herbicidal activity against ALOMY, APESV and ECHCG.
• the compounds according to the invention applied by the post-emergence method, showed very good herbicidal activity.
• Example 1 At an application rate of 1.0 kg/ha, the compound of Example 1 (main isomer 1) applied by the post-emergence method, showed very good herbicidal activity against AMARE, CHEAL, ECHCG and SETVI.
• Example 2 the compound of Example 1 (minor isomer 2), applied by the post-emergence method, showed very good herbicidal activity against ALOMY, APESV and ECHCG.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Agronomy & Crop Science (AREA)
• Pest Control & Pesticides (AREA)
• Plant Pathology (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Dentistry (AREA)
• General Health & Medical Sciences (AREA)
• Wood Science & Technology (AREA)
• Zoology (AREA)
• Environmental Sciences (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
• Plural Heterocyclic Compounds (AREA)
• Hydrogenated Pyridines (AREA)

Applications Claiming Priority (3)

Publications (1)

Family

ID=39832461

Family Applications (1)

Country Status (26)

Cited By (6)

Families Citing this family (35)

Citations (6)

• 2008
  • 2008-06-11 RS RSP-2010/0033A patent/RS51224B/sr unknown
  • 2008-06-11 SI SI200830010T patent/SI2054394T1/sl unknown
  • 2008-06-11 JP JP2010511629A patent/JP2010529168A/ja not_active Withdrawn
  • 2008-06-11 BR BRPI0812877-4A2A patent/BRPI0812877A2/pt not_active Application Discontinuation
  • 2008-06-11 US US12/663,781 patent/US20100173777A1/en not_active Abandoned
  • 2008-06-11 TW TW097121793A patent/TW200906805A/zh unknown
  • 2008-06-11 ES ES08760876T patent/ES2336390T3/es active Active
  • 2008-06-11 DK DK08760876.6T patent/DK2054394T3/da active
  • 2008-06-11 PL PL08760876T patent/PL2054394T3/pl unknown
  • 2008-06-11 KR KR1020107000613A patent/KR20100018065A/ko not_active Application Discontinuation
  • 2008-06-11 CN CN200880019741A patent/CN101679316A/zh active Pending
  • 2008-06-11 EP EP08760876A patent/EP2054394B1/de active Active
  • 2008-06-11 AU AU2008263901A patent/AU2008263901A1/en not_active Abandoned
  • 2008-06-11 UY UY31140A patent/UY31140A1/es unknown
  • 2008-06-11 CA CA2689529A patent/CA2689529A1/en not_active Abandoned
  • 2008-06-11 PT PT08760876T patent/PT2054394E/pt unknown
  • 2008-06-11 EA EA200901659A patent/EA200901659A1/ru unknown
  • 2008-06-11 DE DE502008000206T patent/DE502008000206D1/de active Active
  • 2008-06-11 PE PE2008000995A patent/PE20090334A1/es not_active Application Discontinuation
  • 2008-06-11 WO PCT/EP2008/057328 patent/WO2008152072A2/de active Application Filing
  • 2008-06-11 AT AT08760876T patent/ATE449085T1/de active
  • 2008-06-11 AR ARP080102494A patent/AR068075A1/es not_active Application Discontinuation
  • 2008-06-12 CL CL2008001751A patent/CL2008001751A1/es unknown
• 2009
  • 2009-11-12 IL IL202074A patent/IL202074A0/en unknown
• 2010
  • 2010-02-15 HR HR20100077T patent/HRP20100077T1/hr unknown
  • 2010-02-17 CY CY20101100156T patent/CY1109821T1/el unknown

Patent Citations (7)

Also Published As

Similar Documents

Legal Events